a) Field of the Invention
This invention relates to the provision of a novel wound-healing agent and a novel method for the screening and provision of the wound-healing agent. More specifically, this invention is concerned with a novel medicament for the healing of wounds, for example, wounds by injuries such as simple incised wounds or cuts; wounds by various accidents or disasters; burns; scalds; bone fractures; tooth extraction wounds; operative wounds caused at affected sites or peripheries thereof during surgical operations such as in cornea vessels and various organs; body epithelial or endothelial ulcers; wounds such as keloids; texture injuries of gastrointestinal mucosae, e.g., gastric mucosa injuries, gastrointestinal ulcers, and mucosal injuries caused by inflammatory intestine diseases; hepatic injuries; bone damages; pseudoarthroses; necrosis of femoral head; ligamentous damages; periodontal damages; vascular damages; myocardial infarction; arterial seleroses; post-PTCA re-perfusion disorders; injuries by drugs or radiations, e.g., stomatitides and mucitis caused by chemotherapy or radiotherapy of cancers; decubiti by some causes such as bed-ridden health for a long period of time; and hemorrhoids. This invention also provides an original in vitro screening system and screening method for the provision of such wound-healing agents.
b) Description of the Related Art
To cure various wounds such as those described above, it is the current circumstance that with respect to injuries, injured parts are disinfected and then applied with a wound-covering material such as wet dressing or dry dressing or sutured with a surgical suture and patients then await until the injuries are healed by spontaneous ability of the their bodies. Recently, measures have been increasingly taken for the positive promotion of tissue repair or regeneration of such wounded parts, including use of "Aviten" (trade mark) or application of a material--which is formed of a matrix of a hyaluronic acid sponge and fragments of collagen or as a cell adhesion molecule, laminin or fibronectin coated on the matrix--to wounded parts.
It is stated that the process of healing of a wound is divided into an inflammation phase, a proliferation phase, granulation phase, and a remodeling phase, cicatrization (scar maturation) phase and proceeds through these phases or stages. In the granular tissue forming phase, formation of fibroblasts, myofibroblasts and new blood vessels is observed. In the cicatrization phase, parallel rearrangement of increased collagen on a skin surface and decrease and reconstruction of the new blood vessels are observed, whereby reorganization of the tissue is conducted. During these phases described above, various growth and/or differentiating factors and cytokines are considered to be produced by and released from various tissues containing fibroblasts, myofibroblasts or vascular endothelial cells, platelets, leukocytes, macrophages and the like and to give important action to the healing of the wound. Use of epidermal growth factors (EGFs) or basic fibroblast growth factors (bFGFs) has therefore started on a trial basis for the healing of apellous wounds or gastrointestinal ulcers (for example, Wolfe, M. M. et al., "Gastroenterology" 106, A212, 1994).
Further, external administration of bFGFs and the like are also being tested on animals with a view to promoting angiogenesis to perfuse cardiac muscle damaged by ischemia or the like.
As has been described above, it is performed actually or on a trial basis for the promotion of the process of healing of a wound to administer to the living body a growth and/or differentiation factor, a growth hormone, a cytokine or an adhesion molecule which takes part in the healing of a wound actually performed in the living body. It is the current situation that such substances are limited only to those derived from the living body.
When one wants to apply these substances, especially proteins for the healing of human wounds, a limitation is imposed on their administration route so that their effects are generally not expected to last over an extended period of time. For EGFs and bFGFs, local administration may be the best method for administration in many instances. Under the circumstances, however, local administration of ointments or the like may be performed first although whole body administration by injection or the like would also be attempted on a trial basis. Further, a growth and/or differentiation factor or a cytokine has a multipotent of functions so that it may exhibit not only wound-healing effects but also other undesired action. Its administration may therefore involve potential problems.
In addition, it is also necessary for the preparation of such a protein to process a human gene by genetic engineering to conduct its expression. Therefore, the protein becomes costly, and is also required to overcome various problems which are expected to arise upon its production as a pharmaceutical.